VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}7/{FeO2}8 Complexes of Isopenicillin N Synthase:  Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes

Brown, Charles A.; Neidig, Michael L.; Neibergall, Matthew B.; Lipscomb, John D.; Solomon, Edward I.

doi:10.1021/ja071364v

Cited by 109 publications

(195 citation statements)

References 39 publications

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“…In the study on IPNS, Brown et al [162] This was done by Lundberg et al [167] who modeled the whole catalytic cycle of IPNS using the B3LYP/MM approach and calculated the free-energy barrier of HAA to be ~12 kcal mol -1 (the experimentally derived value is ~17 kcal mol general, a better oxidant than ferryl compounds and in fact its oxidation power strongly depends on the HAA reaction energy. Namely, they showed that for both types of oxidants, the HAA activation energies correlate well with reaction energies, thus obeying the BEP principle (see also section 3.2.5).…”

Section: Mononuclear Ferric-hydroperoxo Active Site: C─h + Hoo─fe IIImentioning

confidence: 99%

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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In this minireview, we provide an account of the current state-of-the-art developments in the area of mono-and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represent a challenge for both experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems.After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods.

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Section: Mononuclear Ferric-hydroperoxo Active Site: C─h + Hoo─fe IIImentioning

confidence: 99%

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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“…Spectroscopic studies highlight the role of charge donation from the ACV thiolate ligand that renders the formation of the ferric superoxo complex energetically more favorable. 22 The six unpaired electrons required to form the septet come from the parallel alignment of the unpaired spin on the superoxide with the spins from the unpaired electron on the superoxo must first flip, but this spin transition does not affect the rate of the reaction. 43 In the quintet spin state, the end-on structure ( 5 2 INT) is the most stable, and this structure is in good alignment to abstract hydrogen from the Cys β-carbon.…”

Section: Transition State For Cys-β-c-h Bond Activationmentioning

confidence: 99%

“…43 In the quintet spin state, the end-on structure ( 5 2 INT) is the most stable, and this structure is in good alignment to abstract hydrogen from the Cys β-carbon. 22 Compared to the active-site model, explicit inclusion of the protein mainly affects the position of the hydrophobic side chain of the valine and the orientation of the amino acid ligands, but has only small effects on the alignment of the reactive superoxide or the cysteine part of the substrate, see After probing the reaction coordinate using the C1-H1 and the O2-H1 distances, (see Figure 3 for labels) a transition state for C-H bond activation ( 5 3 TS) could be fully optimized in the "fully coupled macro/micro-iterative" optimization scheme. The same method, i.e., initial mapping of the reactive space using one or two reaction coordinates followed by full optimization, has been used for all transition states.…”

Section: Transition State For Cys-β-c-h Bond Activationmentioning

confidence: 99%

“…16 Isopenicillin N synthase is a member of a family of mononuclear non-heme iron enzymes with a 2-His-1-carboxylate iron-binding motif. [17][18][19] It uses the four-electron oxidative power of 21 ferrous iron, which gives a ferric superoxo species 22 that activates the cysteine β-C-H bond leading to formation of an iron-bound peroxide. 23 According to the proposal in reference 20, the peroxide abstracts the valine N-H proton to generate the ferryl-oxo and a water molecule.…”

Section: Introductionmentioning

confidence: 99%

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Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Lundberg

Kawatsu

Vreven

et al. 2008

J. Chem. Theory Comput.

117

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Abstract.To highlight the role of the protein in metal enzyme catalysis, we optimize ONIOM QM:MM transition states and intermediates for the full reaction of the non-heme iron enzyme isopenicillin N synthase (IPNS). Optimizations of transition states in large protein systems are possible using our new geometry optimizer with quadratic coupling between the QM and MM regions. [Vreven, T. et. al., Mol. Phys. 2006, 104, 701-704]. To highlight the effect of the metal center, results from the protein model are compared to results from an active site model containing only the metal center and coordinating residues [Lundberg, M. et. al., Biochemistry 2008, 47, 1031-1042. The analysis suggests that the main catalytic effect comes from the metal center, while the protein controls the reactivity to achieve high product specificity. As an example, hydrophobic residues align the valine substrate radical in a favorable conformation for thiazolidine ring closure and contribute to product selectivity and high stereospecificity.

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“…The reduced oxygen then undergoes O-O bond cleavage to yield a molecule of water and leave an Fe(IV)=O species as in the 2-oxoacid dioxygenases or tetrahydropterin-linked hydroxylases. Finally, the high valent iron species is used as a reagent to complete a second part of the reaction, and in doing so, accepts two more electrons to form the second molecule of water.Some well-studied examples of 2-His+Asp/Glu oxidases are isopenicillin N-synthase (IPNS) [79][80][81] , fosfomycin synthase (FOS) 82,83 , and 1-aminocyclopropane-1-carboxylate oxidase (ACCO), which catalyzes the formation of ethylene, a hormone in plants [84][85][86] . These enzymes activate O 2 and ultimately form water using either 4 electrons from substrate (IPNS), two from substrate and two from NADH (FOS), or two from substrate and 2 from ascorbate (ACCO).…”

mentioning

confidence: 99%

Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

2008

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Oxidase and oxygenase enzymes allow the use of relatively unreactive O 2 in biochemical reactions. Many of the mechanistic strategies employed in nature for this key reaction are represented within the 2-His-1-carboxylate facial triad family of non-heme Fe(II) containing enzymes. The open face of the metal coordination sphere opposite the three endogenous ligands participates directly in the reaction chemistry. Here, data from several studies are presented showing that reductive O 2 activation within this family is initiated by substrate (and in some cases co-substrate or cofactor) binding, which then allows coordination of O 2 to the metal. From this starting point, both the O 2 activation process and the reactions with substrates diverge broadly. The reactive species formed in these reactions have been proposed to encompass four oxidation states of iron and all forms of reduced O 2 as well as several of the reactive oxygen species that derive from O-O bond cleavage.Dioxygen serves at least three quite different roles that profoundly impact aerobic life. The most commonly appreciated role is to serve as the terminal electron acceptor in processes such as oxidative phosphorylation that yield the central energy-rich molecules used throughout metabolism. The second, no less important role is to serve as the source for many of the oxygen atoms found in the essential molecules of biological systems such as steroid hormones, aromatic amino acids, neurotransmitters, signalling molecules, and regulatory factors 1 . Also, processes operating on a global scale, such as the recovery of the enormous quantities of carbon sequestered as lignin in plant life or the oxidation of the billions of tons of methane generated by anaerobes before it can enter the atmosphere, also involve oxygen incorporation from O 2 2 ,3 . On a more local scale, biodegradation of both aliphatic and aromatic toxic compounds often begins with the incorporation of oxygen 4 . The third, and least appreciated role played by dioxygen in aerobic organisms involves neither energy conversion nor oxygen incorporation. Rather, some enzymes can convert dioxygen to alternative forms that are, in effect, highly specialized reagents that are used to catalyze the synthesis of important biomolecules. An excellent example of the latter role for O 2 is the biosynthesis of penicillintype antibiotics 5,6 , which is discussed in more detail later in this review.Dioxygen is an attractive reagent for use in a biological system because its high potential reactivity is held in check by its molecular structure. The triplet ground state of O 2 that results from the presence of two unpaired electrons in degenerate molecular orbitals makes the direct reaction with singlet molecules, the spin-paired state of most potential reaction partners, a forbidden process 7 . The central question that has faced chemists and biochemists for the half Competing Interests StatementThe authors declare no competing financial interests. Of course, the answers to this question are of fundam...

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VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}⁷/{FeO₂}⁸ Complexes of Isopenicillin N Synthase: Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes

Cited by 109 publications

References 39 publications

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

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